Drugs deriv with chloroformates

Sadana and Gaonkar described a simultaneous derivative spectroscopic method for the determination of diloxanide furoate and tinidazole in pharmaceutical dosage forms [26]. Drugs were powdered and dissolved in methanol, and the solution set aside for 30 minutes with frequent shaking. After filtration, the filtrate and washings were diluted with methanol. A suspension equivalent to 150 mg of diloxanide furoate was extracted with chloroform. The filtered extract was evaporated to dryness, and the... 

Gardner-Thorpe et al (36) determined primidone and a number of other tntiepileptic drugs in plasma by gas chromatography. The drugs were extracted from acidified plasma samples with chloroform and injected without preparing derivatives. These investigators obsei ved 30 percent recovery of primidone from plasma by their technique. 

Chloroformates 65 of 4-substituted ben2yl alcohols 64, intermediates for berrzyl carbamate disulfide drug derivatives, have been prepared with diphosgene in dioxane/pyridine [42]. 

Thomas et al. (1981) quantified sulfamethazine in swine tissues at 0.1 ppm by densitometry of the fluorescamine derivative on preadsorbent silica gel layers. Tissue was extracted with ethyl acetate, and the drug was back extracted into methylene chloride, and concentrated. Samples and standards were developed with chloroform-tertiary butanol (80 20). 

Musumarra et al. [44] also identified miconazole and other drugs by principal components analysis of standardized thin-layer chromatographic data in four eluent systems and of retention indexes on SE 30. The principal component analysis of standardized R values in four eluents systems ethylacetate-methanol-30% ammonia (85 10 15), cyclohexane-toluene-diethylamine (65 25 10), ethylacetate-chloroform (50 50), and acetone with plates dipped in potassium hydroxide solution, and of gas chromatographic retention indexes in SE 30 for 277 compounds provided a two principal components model that explains 82% of the total variance. The scores plot allowed identification of unknowns or restriction of the range of inquiry to very few candidates. Comparison of these candidates with those selected from another principal components model derived from thin-layer chromatographic data only allowed identification of the drug in all the examined cases. 

Zheng and Sun [67] used a thin-layer chromatographic method for the analysis of primaquine and other quinoline derivatives. The drug and other compounds were chromatographed on silica gel GF254 plate, with methanol aqueous 25 28% ammonia (200 3) and chloroform dichloromethane diethylamine (4 3 1), as mobile phases. Spots were located under ultraviolet radiation. The detection limit was 12 pg/mL. Total separation could be achieved by the use of two plates and the respective mobile phase. 

Further substitution on this compound leads to a somewhat more potent antinema-todal drug. Nitration of (53-6) under the usual conditions leads to the corresponding nitro derivative (54-1). The nitro group is then reduced to the corresponding amine (54-2). Acylation with isopropyl chloroformate forms the corresponding carbamate and thus cambendazole (54-3) [57]. 

A more comprehensive approach was reported in 1975 by Brabander and Verbeke (612). In this method, tissue samples were extracted with methanol and the acidified extract defatted with petroleum ether to be loaded onto a Dowex 50W-X8 anion-exchange resin. Following elution with aqueous methanol, the concentrated buffered extract was further defatted with diethyl ether. The sample was derivatized with 7-chloro-4-nitrobenzo-2-oxa-l,3-diazole (NBD-Cl) to be further spotted on a silica high-performance thin-layer chromatographic plate developed in two dimensions using chloroform/ethanol and chloroform/propionic acid consecutively as eluents. Detection of the propylthiouracil, phenylthiouracil, and tapazole residues was carried out on the basis of the fluorescence induction of the NBD derivatives of the drugs with an alkaline cysteine solution. 

Codeine, also known as methylmorpliine, C H2 NOt H20, is a colorless white crystalline substance, mp 154.9 C, slightly soluble in water, soluble in alcohol and chloroform, effloresces slowly in dry air. Codeine is derived from opium by extraction or by the methylation of morphine. For medical use, codeine is usually offered as the dichlotide, phosphate, or sulfate. Codeine is habit forming. Codeine is known to exacerbate urticaria (familiarly known as hives). Since codeine is incorporated in numerous prescription medicines for headache, heartburn, fatigue, coughing, and relief of aches and pains, persons with a history of urticaria should make this fact known to their physician. Codeine is sometimes used ill cases of acute pericarditis to relieve severe chest pains in early phases of disease. Codeine is sometimes used in drug therapy of renal (kidney) diseases. 

The uses of constant-current coulometry for the determination of drugs in biological fluids are few, basically due to sensitivity restriction. Monforte and Purdy [46] have reported an assay for two allylic barbituric acid derivatives, sodium seconal and sodium sandoptal, with electrogenerated bromine as the titrant and biamperometry for endpoint detection. Quantitative bromination required an excess of bromine hence back titration with standard arsenite was performed. The assay required the formation of a protein-free filtrate of serum with tungstic acid, extraction into chloroform, and sample cleanup by back extraction, followed by coulometric titration with electrogenerated bromine. The protein precipitation step resulted in losses of compound due to coprecipitation. The recoveries of sodium seconal and sodium sandoptal carried through the serum assay were approximately 81 and 88%, respectively. Samples in the concentration range 7.5-50 pg/mL serum were analyzed by this procedure. 

TLC separation of DNS-amines is usually made on layers of silica gel with solvents covering a range of polarity, e.g., chloroform, ethyl acetate, diisopropyl ether and methanol. Seiler and Wiechmann [97] developed 30 solvent systems for the separation of DNS derivatives of over 100 biogenic amines on TLC plates of silica gel. The selective reaction of DNS-C1 with the amino group of catecholamines has been examined [98]. The drugs dopamine, norepinephrine and epinephrine are adsorbed on alumina which protects their hydroxyl groups from dansylation. The N-dansylated compounds are separated with benzene-dioxane-acetic acid (90 25 4) on layers of silica gel. 

Dextran carbamate derivatives. Activation of dextran with 4-nitro-phenyl chloroformate and subsequent reaction with amines leads to the formation of the corresponding carbamate derivatives 2-Hydroxypro-pylamine was selected as a model for amine type drugs. 

The Chemical Development Drug Evaluation branch of Johnson Johnson Pharmaceutical Research Development LLC in Raritan, USA, performed the exothermic reaction of methyl chloroformate with amines to methyl carbamates [34]. Owing to large heat release, hot spots occur. For the reaction of N-methoxycarbonyl-L-ferf-leucine with methyl chloroformate to the amino acid derivative, it is even observed at laboratory scale. 

The use of second-derivative synchronous fluorescence spectrometry was reported by Ruiz et al. [42] to develop a simple, rapid and sensitive fluorimetric method for the determination of binary mixtures of the nonsteroidal antiinflammatory drugs flufenamic (FFA), meclofenamic (MCFA) and mefenamic (MFA) acids in serum and in pharmaceutical formulations. The method is based on the intrinsic fluorescence of these compounds in chloroform. A differential wavelength of 105 nm was used for the resolution of FFA-MFA and MFA-MCFA mixtures, whereas the FFA-MCFA mixture was determined at a differential wavelength of 40 nm. Serum samples were treated with trichloroacetic acid to remove the proteins, and the analytes were extracted in chloroform prior to determination. Pharmaceutical preparations were analyzed without prior separation steps. 

Amphetamines and Other Volatile Bases The extract from stomach contents or urine is examined on two independent columns using 2,5% SE-30 on Chromosorb G (System GA, p. 192), and 10% Apiezon L with 2% potassium hydroxide on Chromosorb W HP (System GB, p. 193). Compounds are identified by reference to retention data derived by chromatographing a solution of pure drugs in chloroform. 

To form the amide derivatives, the acid and amine are condensed in the presence of such agents as N,N -carbonyldiimidazole (18) or a carbodiimide and 1-hydroxybenzotriazole (17). The amides can also be formed via the add chlorides (200,201). Bjorkman (199) described a novel approach to the formation of diastereomeric amides The NSAID indoprofen was coupled by means of ethyl chloroformate to L-leucinamide in a reaction that is complete in 3 min. The derivatives were separated by RP LC, and the procedure was used to study the disposition of the drug in surgical patients (199). Others have adopted this derivatization scheme (209). The chloroformate activation method has also been used with (R)-[42] for resolution of several acids (210). It was found that when hydroxyacids were derivatized, not only did the reaction produce the desired amide moiety at the carboxyl group, but the hydroxyl group was converted to the carbonate derivative of the chloroformate (210). 

Consider the three barbituric acid derivatives thiopental, secobarbital, and barbital with respective pKa of 7.6, 7.9, and 7.8. These drugs are very weak acids. On the basis of their ionization constants we would expect very little difference in their absorption rates from the stomach, yet the drugs are absorbed at very different rates. The reason becomes apparent when the partition coefficients between chloroform and water are considered. Thiopental s value is over 100, whereas the values of secobarbital and barbital are 23 and 0.7, respectively. Now which would one predict to be the least rapidly absorbed and which the most By considering only one physicochemical parameter and excluding others, erroneous conclusions can result. Figure 1-2 illustrates a hypothetical relationship of biological activity as a function of pH only. 

R, S )-2-(p-Chlorophenyl )-a-methyl-5-benzoxazoleacetyl chloride can be used similarly to chloroformates and sulphonyl chlorides. It reacts with primary and secondary amines and with alcohols. Excitation and emission maxima are at 310 nm and 365 nm, respectively. Solvents for the TLC and HPLC separation the derivatives of a number of amines and drugs have been reported [191]. 

As many biologically important analytes do not exhibit efficient detection properties (UV or visible light absorption, fluorescence, or electrochemical activity), their detection limits are relatively low. For example, drugs with chiral centers exist naturally in racemic mixtures that are optically inactive due to the nearly equal proportion of the enantiomers. The determination of enantiomeric purity is of paramount importance in the pharmaceutical industry as each enantiomer may have different therapeutic characteristics. Currently, a method that offers multiple advantages for chiral separations is by converting enantiomers to diastereomers by precolumn derivatization with a pure fluorescent enantiomer. For instance, propranolol existing in racemic form may be analyzed by precolumn derivatization with (+ )-l-(9-fluorenyl)ethyl chloroformate. Well correlated calibration plots were found up to 400pmol and a reproducibility of <2% for each derivative. 

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